We plan a group of closely integrated studies on the electrophysiological and structural abnormalities that cause cardiac arrhythmias so that we will obtain a complete understanding of the mechanisms for arrhythmias resulting from reentrant excitation, afterdepolarizations and abnormal automaticity. We plan to investigate the actions of antiarrhythmic drugs so that we will learn the specific effects of selected agents on reentrant excitation in different types of circuits, on early and delayed afterdepolarizations and on normal and abnormal automaticity. We will characterize the responses of arrhythmias caused by each mechanism to electrophysiological tests like those used in the clinic and to antiarrhythmic drugs with known mechanisms of action. The planned investigation will include studies on the biophysics and pharmacology of single ion channels in the sarcolemma of disaggregated muscle cells and Purkinje fibers through the use of patch and voltage clamp, studies on the electrophysiology and pharmacology of single cardiac cells and isolated preparations of normal and abnormal cardiac tissue through the use of intracellular electrodes, voltage clamp and ion sensitive intracellular and extracellular electrodes and studies on arrhythmias caused by specific mechanisms in the in situ canine atria and ventricles. For these we will employ large numbers of recording electrodes, multiplexing techniques and computer-assisted data acquisition and analysis. A major emphasis will be placed on arrhythmias caused by ischemia and infarction, hypertrophy and digitalis intoxication. Studies on electrophysiology and pharmacology will be correlated with data obtained through investigations of pathology and ultrastructure. The long term goal is to develop means by which selected antiarrhythmic drugs and electrophysiological tests can be used to precisely identify the cause of arrhythmias of the human heart and in this manner improve the accuracy of diagnosis and effectiveness of treatment.